16-89098761-T-C

Variant names:

• chr16-89098761-T-C
• rs189625890
• NM_001243279.3:c.-23T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_001243279.3(ACSF3):​c.-23T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 454,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: ACSF3 NM_001243279.3 splice_region
• Scores: Splicing: ADA: 0.00003359
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130

Genes affected

ACSF3 (HGNC:27288): (acyl-CoA synthetase family member 3) This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity. Mutations in this gene are a cause of combined malonic and methylmalonic aciduria. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSF3	NM_001243279.3	c.-23T>C		splice_region_variant	Exon 2 of 11	ENST00000614302.5	NP_001230208.1
ACSF3	NM_001243279.3	c.-23T>C		5_prime_UTR_variant	Exon 2 of 11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5	c.-23T>C		splice_region_variant	Exon 2 of 11	5	NM_001243279.3	ENSP00000479130.1
ACSF3	ENST00000614302	c.-23T>C		5_prime_UTR_variant	Exon 2 of 11	5	NM_001243279.3	ENSP00000479130.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 363 AN: 152240 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00205 AC: 267 AN: 130506 Hom.: 1 AF XY: 0.00195 AC XY: 139 AN XY: 71230

Gnomad AFR exome AF: 0.000822

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00432

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00286 AC: 862 AN: 301804 Hom.: 4 Cov.: 0 AF XY: 0.00265 AC XY: 455 AN XY: 172002

Gnomad4 AFR exome AF: 0.000585

Gnomad4 AMR exome AF: 0.000843

Gnomad4 ASJ exome AF: 0.00426

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000335

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152358 Hom.: 1 Cov.: 34 AF XY: 0.00199 AC XY: 148 AN XY: 74510

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00260

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 17, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-23 T>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.-23 T>C variant is observed in 34/8,172 (0.4%) alleles from individuals of Ashkenazi Jewish background and in one apparently homozygous individual in the ExAC dataset (Lek et al., 2016). The c.-23 T>C variant is located within the 5' UTR of the ACSF3 gene at a position that is conserved across species; regulatory variants of the ACSF3 gene have not been previously reported as pathogenic to our knowledge (Stenson et al., 2014). However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.43
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs189625890; hg19: chr16-89165169;